Omeprazole, chemically 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole and its therapeutic uses are disclosed in European Patent No. 5129. Omeprazole is a well-known gastric acid secretion inhibitor, and is useful as an anti ulcer agent. Omeprazole has a stereogenic center at sulfur and therefore exist as two optical isomers such as R-omeprazole and S-omeprazole (esomeprazole).
PCT Publication No. WO 94/27988 disclosed certain salts (sodium, magnesium, lithium, potassium, calcium and alkyl ammonium salts) of single enantiomers of omeprazole and processes for their preparation thereof. These compounds have improved pharmacokinetic and metabolic properties which will give an improved therapeutic profile such as a lower degree of interindividual variation.
PCT Publication No. WO 96/02535 disclosed a process for the preparation of the single enantiomers of omeprazole and structurally related compounds as well as salts thereof.
PCT Publication No. WO 98/28294 disclosed esomeprazole in an amorphous form, a partly crystalline form A, and a substantially crystalline form B.
U.S. Pat. No. 6,369,085 (herein after referred to as the '085 patent) described crystalline forms of esomeprazole magnesium (esomeprazole magnesium dihydrate Form A, esomeprazole magnesium dihydrate Form B, esomeprazole magnesium trihydrate and esomeprazole potassium) and characterizes them by powder X-ray Diffraction (P-XRD).
According to the '085 patent, esomeprazole magnesium dihydrate Form A is characterized by an X-ray powder diffraction pattern having peaks expressed as d-value at approximately 3.04, 3.14, 3.18, 4.05, 4.19, 4.32, 4.54, 4.69, 5.2, 5.3, 5.8, 6.2, 6.6 and 15.5 A° (Angstrom units); esomeprazole magnesium dihydrate Form B is characterized by an X-ray powder diffraction pattern having peaks expressed as d-value at approximately 4.19, 4.45, 4.68, 4.79, 4.91, 4.98, 5.1, 5.4, 5.5, 5.6, 5.8, 6.3, 6.7, 7.9, 8.1, 11.0, 11.8 and 14.9 A°; esomeprazole magnesium trihydrate is characterized by an X-ray powder diffraction pattern having peaks expressed as d-value at approximately 2.67, 2.79, 3.27, 3.52, 3.82, 3.96, 4.14, 5.2, 5.6, 6.7, 6.9, 8.3 and 16.6 A°; and esomeprazole potassium is characterized by an X-ray powder diffraction pattern having peaks expressed as d-value at approximately 2.31, 2.38, 2.40, 2.43, 2.45, 2.47, 2.52, 2.56, 2.57, 2.58, 2.66, 2.71, 2.76, 2.85, 2.89, 2.93, 2.97, 3.03, 3.06, 3.12, 3.20, 3.28, 3.34, 3.38, 3.42, 3.52, 3.55, 3.60, 3.74, 3.81, 3.87, 3.89, 3.92, 3.98, 4.27, 4.32, 4.42, 4.52, 4.71, 4.75, 5.0, 5.2, 5.3, 5.4, 5.8, 6.1, 6.2, 6.5, 6.8, 7.8, 10.6 and 13.6 A°.
The alkaline salts of omeprazole and (S)-enantiomer of omeprazole (esomeprazole), the pharmaceutical preparations of these salts and the method of treatment of gastric acid-related diseases using them are disclosed in U.S. Pat. Nos. 4,738,974, 5,877,192 and 5,714,504.
PCT Publication No. WO 2004/076440 A1 described crystalline forms, Form I and Form II, of esomeprazole, and its hydrates. PCT Publication No. WO 2004/020436 A1 described amorphous hydrates of esomeprazole magnesium and process for their preparation. PCT Publication No. WO 2004/002982 A2 described amorphous form esomeprazole free base and process for its preparation.
Esomeprazole magnesium dihydrate obtained by the process described in the art, has an important draw back of the being less assayed, and is contaminated with esomeprazole magnesium trihydrate form.
According to the prior art processes, esomeprazole magnesium dihydrate is obtained by using either wet esomeprazole magnesium isolated from aqueous medium, or esomeprazole magnesium trihydrate.
Extensive experimentation is carried out by the present inventors to find the way to eliminate the trihydrate contamination and to prepare high assayed esomeprazole magnesium dihydrate. As a result, it has now been found that high assayed esomeprazole magnesium dihydrate substantially free of its trihydrate impurity can be prepared. The present invention uses neither wet esomeprazole magnesium nor esomeprazole magnesium trihydrate for the preparation of esomeprazole magnesium dihydrate and thereby the present invention could yield esomeprazole magnesium dihydrate substantially free of its trihydrate form.
One object of the present invention is to provide a high assayed esomeprazole magnesium dihydrate substantially free of its trihydrate form.
According to another object of the present invention is to provide an improved and commercially viable process for preparation of high assayed esomeprazole magnesium dihydrate substantially free of its trihydrate form.
Another object of the present invention is to provide an improved process for preparation of pure amorphous esomeprazole magnesium.
According to another object of the present invention is to provide an improved and commercially viable process for preparation of substantially enantiomerically pure esomeprazole in neutral form or as a pharmaceutically acceptable salt or as its solvates including hydrates.
According to another object of the present invention is to provide a solid form of esomeprazole calcium salt.
According to another object of the present invention is to provide stable and novel crystalline forms of esomeprazole calcium salt, processes for preparing them and pharmaceutical compositions comprising them.
According to another object of the present invention is to provide a stable and novel amorphous form of esomeprazole calcium salt, process for preparing it and a pharmaceutical composition comprising it.